Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy

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• 作者：Kevin M. Sokolowski ; M.D. ; Mariappan Balamurugan ; Ph.D. ; Selvi Kunnimalaiyaan ; M.S. ; Jacob Wilson ; B.S. ; Thomas Clark Gamblin ; M.D. ; M.S. ; M.B.A. ; F.A.C.S. ; ^{tcgamblin@mcw.edu" class="auth_mail" title="E-mail the corresponding author} ; Muthusamy Kunnimalaiyaan ; Ph.D. ; ^{mkunnima@mcw.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Akt ; MK2206 ; Notch ; Dual target ; Hepatocellular carcinoma
• 刊名：The American Journal of Surgery
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：211
• 期：4
• 页码：755-760
• 全文大小：518 K

文摘

We have shown that an Akt inhibitor, MK2206, reduces hepatocellular carcinoma (HCC) proliferation. To further delineate MK2206, we sought to investigate the Notch1 pathway and hypothesize that MK2206 treatment will result in Notch1 inhibition with either subsequent or parallel Akt suppression.

Methods

HCC cell lines were treated with various concentrations of MK2206. Cell proliferation was determined via real-time live cell imaging. Knockdown of Notch1 was used to observe interaction between Notch1 and pAkt. Cell lysates were analyzed via Western blotting for Notch and Akt pathway targets.

Results

After treatment with MK2206 (up to 2 μM), there was a 60% reduction in cell viability at 48 hours with a concomitant reduction in Notch1 expression. Knockdown of Notch1 in HCC cell lines correlated with reduction in Akt phosphorylation.

Conclusions

MK2206 inhibits both the PI3-K/Akt and Notch1 pathways. Therefore, further characterization of MK2206 comparing the 2 pathways is warranted and the effect of dual targeting in HCC.